PROJECT SUMMARY/ABSTRACT Our overall objective of this competitive revision is to systematically investigate the effects of sex (female vs. male) on biomechanical, functional and OA-related outcomes of bridge-enhanced ACL repair in a validated large animal model. Young women are particularly vulnerable to anterior cruciate ligament (ACL) tears, with an increased risk of 2 to 10 times that of young men. Recent clinical studies have also shown that women have significantly worse functional and patient reported outcomes than men after ACL reconstruction surgery, a procedure in which the torn ACL is replaced by a graft of tendon. The mechanisms of these sex-specific discrepancies remain unknown and will be addressed in this study. In an effort to improve outcomes following ACL reconstruction, we have developed a novel bridge-enhanced ACL repair procedure in which a suture repair of the torn ligament is augmented with a tissue-engineered scaffold to stimulate healing. While the preclinical results of this procedure have been promising, the discrepancies in ACL healing between men and women persist. The proposed revision will address three aims; 1) To determine the sex-specific differences in healing ACL mechanical properties at multiple time points up to 24 weeks after ACL surgery; 2) To determine the sex-specific differences in functional and OA-related outcomes of bridge-enhanced ACL repair at multiple time points up to 24 weeks after surgery; and 3) Identify the potential mechanical contributors to the inferior functional and OA-related outcomes in females following bridge-enhanced ACL repair. The improved understanding of sexual dimorphism in the ACL healing response is critical to the development of the bridge-enhanced ACL repair procedure, which is in the process of being translated from bench to bedside with limited data on how it will respond in each sex (the first-in-human trial for this novel procedure is currently underway [NCT02292004]). The results of this competitive revision will lay the foundation for future scientific efforts to further optimize this emerging surgical technique and its postoperative rehabilitation regimen for each sex, which may lead to improved outcomes in particular among women. This supplemental study will benefit from the resources provided by the recently funded parent grant (R01-AR065462), which is aimed at assessing ligament healing in vivo over time using MR imaging and biomechanical testing. With this competing supplement, we will increase the number of animals by adding a group of female animals and conducting the analyses to address the aims of this revision. This addition will enable us to compare biomechanical, functional and OA-related outcomes of bridge-enhanced ACL repair between male and female pigs as well as continuing to meet the original aims of the parent grant.